MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer

Several lines of evidence suggest that altered adenosine deaminase (ADA) activity, especially its ADA2 iso-enzyme, is associated with malignant breast cancer (BC) development. Triple-negative breast cancer (TNBC) is currently the most challenging BC subtype due to its metastatic potential and recurrence. Herein, we analyzed the sources of ADA iso-enzymes in TNBC by investigating the effects of cell-to-cell interactions between TNBC cells, macrophages, lymphocytes, and endothelial cells. We also examined the potential relationship between ADA activity and cancer progression in TNBC patients. In vitro analyses demonstrated that the interactions of immune and endothelial cells with MDA-MB-231 triple negative BC cells modulated their extracellular adenosine metabolism pattern. However, they caused an increase in the ADA1 activity, and did not alter ADA2 activity in cancer cells. In turn, the co-culture of MDA-MB-231 cells with THP-1 monocyte/macrophages, Jurkat cells, and human lung microvascular endothelial cells (HULEC) caused the increase in ADA2 activity on THP-1 cells and ADA1 activity on Jurkat cells and HULEC. Clinical sample analysis revealed that TNBC patients had higher plasma ADA2 activities and lower ADA1/ADA2 ratio at advanced stages of cancer development than in the initial stages, while patients with hormone receptor positive, HER2 negative (HR+HER2-), and triple positive (HR+HER2+) breast cancers at the same stages showed opposite trends. TNBC patients also demonstrated positive associations between plasma ADA2 activity and pro-tumor M2 macrophage markers, as well as between ADA1 activity and endothelial dysfunction or inflammatory parameters. The analysis of TNBC patients, at 6 and 12 months following cancer treatment, did not showed significant changes in plasma ADA activities and macrophage polarization markers, which may be the cause of their therapeutic failure. We conclude that alterations in both ADA iso-enzymes can play a role in breast cancer development and progression by the modulation of extracellular adenosine-dependent pathways. Additionally, the changes in ADA2 activity that may contribute to the differentiation of macrophages into unfavorable pro-tumor M2 phenotype deserve special attention in TNBC.

Download Full-text

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Integrative Cancer Therapies ◽

10.1177/1534735420949678 ◽

2020 ◽

Vol 19 ◽

pp. 153473542094967

Author(s):

Min Kyoon Kim ◽

Yesl Kim ◽

SeungHwa Park ◽

Eunju Kim ◽

Yerin Kim ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

High Fat Diet ◽

Tumor Volume ◽

Macrophage Polarization ◽

M2 Macrophage ◽

High Fat ◽

Low Intensity ◽

M2 Macrophage Polarization ◽

Low Intensity Exercise

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

Download Full-text

17P BCL6 and Notch pathway: A signaling axis leading to a novel druggable biotarget in triple-negative breast cancer

Annals of Oncology ◽

10.1016/j.annonc.2021.01.030 ◽

2021 ◽

Vol 32 ◽

pp. S8

Author(s):

F. De Santis ◽

S.L. Romero-Cordoba ◽

L. Castagnoli ◽

T. Volpari ◽

S. Faraci ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Notch Pathway ◽

Signaling Axis

Download Full-text

Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

Oncotarget ◽

10.18632/oncotarget.9885 ◽

2016 ◽

Vol 7 (31) ◽

pp. 49349-49367 ◽

Cited By ~ 36

Author(s):

Wei Bin Fang ◽

Min Yao ◽

Gage Brummer ◽

Diana Acevedo ◽

Nabil Alhakamy ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Gene Silencing ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

M2 Macrophage ◽

Cell Renewal ◽

Stem Cell Renewal

Download Full-text

In vivo β-catenin attenuation by the integrin α5-targeting nano-delivery strategy suppresses triple negative breast cancer stemness and metastasis

Biomaterials ◽

10.1016/j.biomaterials.2018.10.019 ◽

2019 ◽

Vol 188 ◽

pp. 160-172 ◽

Cited By ~ 21

Author(s):

Yunfei Li ◽

Yajuan Xiao ◽

Hsuan-Pei Lin ◽

Derek Reichel ◽

Younsoo Bae ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cancer Stemness ◽

Delivery Strategy ◽

Integrin Α5

Download Full-text

Response to FEC Chemotherapy and Oncolytic HSV-1 Is Associated with Macrophage Polarization and Increased Expression of S100A8/A9 in Triple Negative Breast Cancer

Cancers ◽

10.3390/cancers13215590 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5590

Author(s):

Alyssa Vito ◽

Nader El-Sayes ◽

Omar Salem ◽

Yonghong Wan ◽

Karen L. Mossman

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Macrophage Polarization ◽

Gene Signature ◽

Immune Checkpoint Blockade ◽

Differential Gene ◽

Microarray Analyses ◽

Tumor Cell Killing

The era of immunotherapy has seen an insurgence of novel therapies driving oncologic research and the clinical management of the disease. We have previously reported that a combination of chemotherapy (FEC) and oncolytic virotherapy (oHSV-1) can be used to sensitize otherwise non-responsive tumors to immune checkpoint blockade and that tumor-infiltrating B cells are required for the efficacy of our therapeutic regimen in a murine model of triple-negative breast cancer. In the studies herein, we have performed gene expression profiling using microarray analyses and have investigated the differential gene expression between tumors treated with FEC + oHSV-1 versus untreated tumors. In this work, we uncovered a therapeutically driven switch of the myeloid phenotype and a gene signature driving increased tumor cell killing.

Download Full-text